Carbazole to indolazepinone scaffold morphing leads to potent cell-active dengue antivirals.

According to WHO, dengue virus is classed among major threats for future pandemics and remains at large an unmet medical need as there are currently no relevant antiviral drugs whereas vaccine developments have met with safety concerns, mostly due to secondary infections caused by antibody-dependant-enhancement in cross infections among the four dengue serotypes. This adds extra complexity in dengue antiviral research and has impeded the progress in this field. Following through our previous effort which born the allosteric, dual-mode inhibitor SP-471P (a carbazole derivative, EC 1.

Meeting report: 34th international conference on antiviral research.

As a result of the multiple gathering and travels restrictions during the SARS-CoV-2 pandemic, the annual meeting of the International Society for Antiviral Research (ISAR), the International Conference on Antiviral Research (ICAR), could not be held in person in 2021. Nonetheless, ISAR successfully organized a remote conference, retaining the most critical aspects of all ICARs, a collegiate gathering of researchers in academia, industry, government and non-governmental institutions working to develop, identify, and evaluate effective antiviral therapy for the benefit of all human beings. This article highlights the 2021 remote meeting, which presented the advances and objectives of antiviral and vaccine discovery, research, and development.

Experimental evidence for a high rate of maternal-fetal transmission of dengue virus in the presence of antibodies in immunocompromised mice.

Background: Congenital disorders associated with prenatal vertical transmission of Zika virus (ZIKV) is well established since the 2016 outbreak in the Americas. However, despite clinical reports of similar mode of transmission for other flaviviruses such as dengue virus (DENV), the phenomenon has not been experimentally explored.

Methods: Pregnant AG129 mice were infected with DENV1 in the presence or absence of enhancing antibodies at different gestational time points.

Amidoxime prodrugs convert to potent cell-active multimodal inhibitors of the dengue virus protease.

The flavivirus genus of the Flaviviridae family comprises Dengue, Zika and West-Nile viruses which constitute unmet medical needs as neither appropriate antivirals nor safe vaccines are available. The dengue NS2BNS3 protease is one of the most promising validated targets for developing a dengue treatment however reported protease inhibitors suffer from toxicity and cellular inefficacy. Here we report SAR on our previously reported Zika-active carbazole scaffold, culminating prodrug compound SP-471P (EC 1.

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain.

Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination.

Cell-active carbazole derivatives as inhibitors of the zika virus protease.

Zika virus (ZIKV) infection recently resulted in an international health emergency the Americas in and despite its high profile there is currently no approved treatment for ZIKV infection with millions of people being at risk. ZIKV is a member of Flaviviridae family which includes prominent members such as dengue virus (DENV) and West Nile virus (WNV). One of the best validated targets for developing anti-flaviviral treatment for DENV and WNV infection is the NS2B/NS3 protease.

A double-blind randomized placebo-controlled trial of probiotics in systemic sclerosis associated gastrointestinal disease.

Objective: Assess whether treatment with probiotics improve gastrointestinal symptoms in patients with systemic sclerosis (SSc).

Methods: In this double-blind randomized placebo-controlled parallel-group phase II trial, SSc subjects with total score ≥ 0.1 on a validated SSc-specific gastrointestinal tract (GIT) questionnaire were randomized (1:1) to receive 60 days of high dose multi-strain probiotics (Vivomixx® 1800 billion units/day) or identical placebo, followed by an additional 60 days of probiotics in both groups.

Porcine hepatocytes culture on biofunctionalized 3D inverted colloidal crystal scaffolds as an model for predicting drug hepatotoxicity.

As drug-induced hepatotoxicity represents one of the most common causes of drug failure, three-dimensional (3D) liver platforms represent a fantastic toolbox to predict drug toxicity and thus reduce animal studies and lessen drug attrition rates. The aim of this study is to establish a functional porcine hepatocyte culture using a biofunctionalized 3D inverted colloidal crystal (ICC) hydrogel platform. The performances of non-adhesive bare poly(ethylene glycol)diacrylate (PEGDA) ICCs and PEGDA ICCs coated with either collagen type I or fibronectin have been investigated.

Do men with normal testosterone-oestradiol ratios benefit from letrozole for the treatment of male infertility?

Research Question: Previous studies of aromatase inhibitors on male infertility have focused on men with low testosterone-oestradiol ratio of less than 10. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone-oestradiol ratio?

Design: Prospective study of men with idiopathic severe oligozoospermia (sperm concentration <5 million/ml) carried out between February 2015 and March 2017. The objective was to assess if semen-analysis parameters improved after treatment with letrozole.

Chromosome 15q11-q13 copy number gain detected by array-CGH in two cases with a maternal methylation pattern.

Background: The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism.